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Law #14.874 was enacted on May 28, 2024, providing guidelines for research involving human subjects and establishing the National System of Ethics in research involving human subjects. This statutory framework is of utmost importance as it defines the rights of volunteers and outlines the responsibilities for researchers and sponsors of clinical research.

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1. Definition of Clinical Research and Clinical Trial

Clinical research involving human subjects is a systematic set of scientific procedures conducted on humans. Its primary objectives are to (i) evaluate the action, safety, and efficacy of drugs, products, techniques, procedures, medical or health care devices for therapeutic, preventive, or diagnostic purposes; (ii) verify the distribution of risk factors, diseases, or illnesses within the population; and (iii) assess the effects of various factors or states on health. In contrast, a clinical trial refers to experimental research conducted on one or more human subjects. Its purpose is to evaluate the safety, clinical performance, or efficacy of a medical devices, experimental drugs or advanced therapies.

Any clinical research carried out on humans in Brazil must meet the following ethical and scientific requirements:

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1. Respect for the rights, dignity, safety, and well-being of research participants must take precedence over scientific and societal interests.

2.  Research should be based on a favorable evaluation of the risk-benefit ratio for both participants and society.

3. The research protocol must have a solid scientific foundation and a clear description.

4.  Research must be conducted according to a protocol approved by the Research Ethics Committee (REC).

5. Professionals involved in the research must possess the necessary competence and technical qualifications.

6. Participants’ participation must be voluntary and based on informed consent.

7. Researchers must respect participants’ privacy and maintain confidentiality of their data and identity.

8. Adequate care must be provided in cases involving interventions.

9. Procedures adopted must ensure technical quality and scientific validity.

10. Research must be conducted in full compliance with good clinical practices.

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For clinical trials, in addition to the ten requirements described above, the following must be observed:

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1. Clinical trials must have access to both clinical and non-clinical information about the product under investigation. This information supports the research process.

2. Researchers must ensure medical care and make decisions in the best interest of the research participant during the trial.

3. Continuous assessment is necessary to adapt or suspend an ongoing study if one intervention proves significantly superior to another.

4. Products under investigation must be produced, handled, and stored according to good manufacturing practices guidelines.

5. Clinical trials should be registered in public databases.

6. Representatives of both sexes and diverse ethnicities should participate when essential for research. This inclusion should not hinder progress and should follow technical-scientific criteria.

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2. National Research Ethics Body and RECs

The Law also set up the National System of Ethics in Research Involving Human Subjects, which is to be regulated by an Executive Order and is split into two parts: (i) the National Research Ethics Body and (ii) the ethical research review, which is represented by the RECs. The responsibilities of the national body and the requirements for the RECs are outlined below:

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RESPONSIBILITIES OF THE NATIONAL RESEARCH ETHICS BODY

1. Draft regulatory standards on research ethics.

2. Assess the effectiveness of the National System of Ethics in Research Involving Human Subjects.

3. Certify the RECs, enabling them to carry out ethical review in research, based on the degree of risk involved.

4. Oversee, assist, and supervise the RECs in terms of analyzing research protocols and adhering to relevant guidelines.

5. Encourage and support the training of REC members, with a particular focus on ethical and methodological aspects.

6. Serve as an appellate body for decisions made by the RECs.

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REQUIREMENTS FOR THE RESEARCH ETHICS COMMITTEES (RECs)

1. Be made up of an interdisciplinary team, spanning medical, scientific, and non-scientific fields. This ensures that the members collectively have the necessary qualifications and experience to analyze all aspects inherent of to the research, including medical, scientific, ethical, and good clinical practice aspects.

2. Be accredited by the national research ethics body.

3. Operate regularly.

4. Have sufficient infrastructure to conduct its activities.

5. Maintain a publicly accessible list of its members, along with their respective professional qualifications.

6. Possess a descriptive document of the adopted operational procedures and keep written records of their activities and meetings.

7. Include a representative of the research participants in its composition.

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The institution hosting the REC will foster and back the training of its committee members, focusing on the ethical and methodological aspects related to the rights of the research participants. Furthermore, the REC's performance will be under the oversight and monitoring of the National Research Ethics Body.

The Responsibilities of the REC are as follows:

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RESPONSIBILITIES OF THE REC

1. Safeguard the rights, safety, and well-being of the research participants, particularly those in vulnerable situations.

2. Evaluate the researcher’s qualifications for the proposed research, based on their academic and professional resume and the documents requested by the committee.

3. Carry out the analysis of the research submitted to it and monitor its execution, observing the minimum frequency defined in regulation, according to the classification of the research and good clinical practices.

4. Request additional information for the research participants when it is deemed essential for the protection of the rights, safety, and well-being of the research participants

5. Ensure that the research project and other documents properly address relevant ethical issues and comply with applicable regulatory requirements, including those related to good practices.

6. Ensure that adequate means are provided for obtaining the consent of the research participant or their legal representative.

7. Ensure that the information regarding prior compensation or material provision to the research participant is clearly specified in the Informed Consent Form (ICF), including the forms, amounts, and their frequency.

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Research involving human subjects will be undergo prior ethical review, conducted by the ethical research review body, adhering to the following principles:

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1. Safeguarding the dignity, safety and well-being of the research participant.

2. Encouraging technical and scientific advancement.

3. Upholding independence, transparency, and publicity.

4. Ensuring fairness in the application of criteria and procedures for analyzing research projects, in line with the risk-benefit ratio outlined in their protocols.

5. Maintaining efficiency and agility in the analysis and issuance of opinions.

6. Promoting multidisciplinarity.

7. Exercising social control, with the participation of a representative of the research participants.

8. Respecting good clinical practices.

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The ethical review of research conducted by the REC, resulting in an opinion, must not exceed a period of 30 business days from the date when all research documents are accepted. The REC must accept or reject these documents within ten business days from the date of submission. Documents resulting from the ethical review process will be retained by the REC for five years following the conclusion of the research. If a decision made by the REC is appealed, the appeal can be made to the Committee itself within 30 days at the administrative level. If the appeal is not resolved at this level, it can then be escalated to the National Research Ethics Body within an additional 30 days.

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3. Participants' authorization to enter the survey

The ICF requires the participant's explicit authorization to ensure their participation in the clinical research. This authorization must be written in an easy-to-understand language and is only valid when dated and signed by both the responsible researcher and the research participant or their legal representative. If the participant is unable to read, an impartial witness must sign the document. The participant’s authorization can be withdrawn at any time without incurring any penalties or harm. The researcher or their designated professional must fully inform the participant or their legal representative of all relevant aspects of the research, including the approval by the REC.

It’s important to note that clinical research must be conducted in a way that ensures the participant’s anonymity and privacy, as well as the confidentiality of information, except when necessary for the analysis of serious adverse events.

Another key point is the prohibition of compensating participants or offering any kind of advantage for their participation in research.  However, this does not include (i) reimbursement of expenses related to transportation or food or the provision of material beforehand, and (ii) other types of necessary reimbursements, according to the research project. On the other hand, this prohibition does not apply to the participation of healthy individuals in Phase I or bioequivalence clinical trials, provided that (i) the participant is enrolled in the national register of volunteers for bioequivalence and Phase I studies, in accordance with regulation, (ii) the participant does not participate in more than one research study at the same time, and (iii) in case of research to assess the maximum tolerated dose or to assess bioavailability and bioequivalence, the research participant must comply with a minimum period of six months from the date of conclusion of research participation before being included in a new clinical trial.

This includes cases where participants are considered vulnerable, meaning they are in a situation where they or a group of people have a diminished capacity to make decisions and resist in the research situation. This can be due to individual, psychological, economic, cultural, social, or political factors. In any of these cases, the consent process for vulnerable situations must be respected. Their participation in the research must is conditional upon (i) the existence of the ICF, signed by a legal or judicial representative, and (ii) the research being essential for the population represented by the vulnerable participant. It must be impossible to obtain data of comparable validity through the participation of adult individuals capable of giving their consent or through the use of other investigative methods.

Both the lead researcher and the representative of the incapacitated person will co-sign a communication to the Prosecution Office, informing them of the incapacitated person's participation in the research.

Research involving pregnant women will only be permitted when the predictable risk to the health of the pregnant or unborn child is minimal. It will also be preceded by similar research involving women who are not pregnant, unless the pregnancy or the unborn child are the primary subjects of the research.

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4. Use of Placebo

The new Law specifies that the exclusive use of a placebo (a formulation without pharmacological effect or a simulated procedure used in control groups of clinical trials for comparison with the intervention under trial) is only permitted when there are no proven methods of prevention, diagnosis, or treatment for the disease being researched, as appropriate. It is also stipulated that the risks or damages resulting from the use of a placebo must not outweigh the benefits of participating in the research.

Furthermore, in clinical trials, as soon as a significant superiority of the experimental intervention over the comparison product or placebo is confirmed, the lead researcher, the independent monitoring committee, or the sponsor must evaluate the need to adjust or suspend the ongoing study in order to best serve the interests of the research participant.

The participant will be compensated by the sponsor for any damages suffered as a result of their participation in the research and will receive the necessary healthcare related to such damages.

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5. Responsibilities of Sponsors and Researchers

The responsibilities of the sponsors are outlined below. The sponsor can delegate the execution of certain tasks to a representative Contract Research Organization (CRO). Additionally, it is recommended that an independent data monitoring committee be established whenever possible. This committee’s role is to periodically review the progress of the research, safety data, and critical efficacy points. Based on their evaluations, they will recommend to the sponsor whether to continue, modify, or discontinue the research.

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RESPONSIBILITIES OF SPONSORS

1. Implement and maintain quality assurance and quality control systems, based on Standard Operating Procedures (POPs), to ensure that research is conducted, and data is generated, documented, and reported in compliance with the protocol, good clinical practice, and regulatory requirements.

2. Establish contracts between all parties involved in the research.

3. Control the quality of each stage of data handling to ensure its reliability and correct processing.

4. Maintain the quality and completeness of the research data, even if some or all tasks have been delegated to third parties.

5. Select researchers and institutions to conduct the research, considering the necessary qualifications for conducting and supervising the research.

6. Guarantee adequate resources for conducting the research, including covering all expenses related to procedures, examinations, and actions for resolving adverse events.

7. Appoint a researcher to be responsible for the clinical decisions related to the research, in the case of a clinical trial.

8. Verify that the research participant has authorized direct access to their data and information for the purposes of monitoring, auditing, review by the competent ethical entities, and inspection by regulatory agencies.

9. Promptly notify the researcher, the executing institution, the competent ethical review bodies, and the health authority about findings that may adversely affect the safety of the research participant, compromise the conduct of the research, or affect the approval granted by the REC.

10. Issue reports on adverse reactions to the drug or experimental products considered serious or unexpected in the case of clinical trials, which must be informed to the institutions and researchers involved and the health authority.

11. Promptly notify the health authority of all serious or unexpected adverse events whose causality is possible, probable, or defined in relation to the product under investigation.

12. Select and train monitors and auditors.

13. Properly monitor the research.

14. Promptly communicate to the researchers involved, the executing institution, and to the health authority about the reasons for the suspension or premature termination of the research, when applicable.

15. Compensate and provide healthcare to the research participant for any damages suffered as a result of their participation in the research.

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The responsibilities of researchers are as follows:

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RESPONSIBILITIES OF RESEARCHERS

1. Possess and demonstrate the necessary qualifications and experience to take responsibility for the proper conduct of the research.

2. Adhere to the standards of good clinical and scientific practices and regulatory requirements.

3. Submit the research documentation, including any amendments, for approval by the REC.

4. Select individuals who are qualified to carry out the tasks related to the research.

5. In the case of a clinical trial, ensure the clinical monitoring of the research participants during the study and after its completion, for the period and under the conditions defined in the protocol approved by the REC.

6. Conduct the research in compliance with the project approved by the REC.

7. When requested, provide direct access to the records and documents of the research to the monitor, auditor, other sponsor representatives, the REC, the national research ethics body, and the health authority.

8. Allow the research to be monitored and audited by the sponsor, as well as inspections by the health authority, the national research ethics body, and the REC that approved it.

9. Annually and whenever requested, present partial reports with information on the progress of the research to the REC that has reviewed it.

10. Promptly communicate all serious or unexpected adverse events to the sponsor, health authority, REC, and national research ethics body.

11. Keep the data and essential documents of the research stored and under their custody, in a physical or digital environment, for a period of five (5) years after its formal conclusion or discontinuation, and for a period of ten (10) years in the case of advanced therapy products.

12. Ensure the rights of research participants and safeguard their well-being and safety.

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6. Continuity of Treatment After Clinical Trial

Before the start of the clinical trial, both the sponsor and the researcher must submit a post-study access plan to REC. This plan should include a presentation and justification of whether or not it is necessary to provide the experimental drug free of charge to the participants who need it after the clinical trial concludes. If there is a need to supply the drug after a clinical trial, a post-study supply program must be prepared in accordance with a specific regulation. This program should be set for a defined period of time and include monitoring of the participant’s safety.

The post-study supply program can only be initiated after regulatory approval. At the end of the clinical trial, the researcher must conduct an individual assessment, in consultation with the sponsor and the research participant, to determine the need to continue the experimental treatment for each participant.

It’s important to clarify that the sponsor is responsible for the free supply of the experimental drug after the clinical trial. This should be carried out whenever it is considered the best therapy or treatment for the clinical condition of the research participant and present a more favorable risk-benefit ratio compared to the other available treatments. This free post-clinical trial supply must be carried out after the end of individual participation and its transition to the post-study supply program.

The above evaluation shall take into account the following criteria:

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CRITERIA FOR EVALUATION BY THE RESEARCHER

1. The severity of the disease and its threat to the continuity of the participant's life.

2. The availability of satisfactory therapeutic alternatives for treating the research participant, considering their location.

3. Whether the experimental drug addresses an unmet clinical need.

4. If the evidence of benefit to the participant outweighs the risk associated with the use of the experimental drug.

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However, the discontinuation of the free supply of the experimental drug within the scope of the post-study supply program can only occur under the following circumstances:

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1. The decision of the research participant themselves or when the research participant cannot validly express their will.

2. Cure of the disease or health problems targeted by the clinical trial, or the introduction of a satisfactory therapeutic alternative, as duly documented by the researcher.

3. Absence of benefit from the continued use of the experimental drug to the research participant, considering the risk-benefit ratio outside the context of the clinical trial or the emergence of new evidence of risks related to the safety profile of the experimental drug, as duly documented by the researcher.

4. Occurrence of adverse reaction that, at the researcher’s discretion, makes the continuation of the experimental drug impossible, even in the face of possible benefits.

5. Impossibility of obtaining or manufacturing the experimental drug due to technical or safety reasons, duly justified, and provided that the sponsor provides an equivalent or superior therapeutic alternative existing on the market.

6. Availability of the experimental drug in the public health system.

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7. Participant Rights in Clinical Research

The following are the rights of participants in clinical research, which must be included in the ICF:

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1. To be properly informed and clarified, in a clear and objective manner, whenever relevant, about the purpose and the potential benefits and risks associated with the disposal of their biological material.

2. To have their physical and mental health and integrity protected during the collection procedures of biological material.

3. To withdraw their consent to the custody and use of the stored human biological material at any time, in writing and signed, without any burden or damage, and the right to receive the samples back.

4. To have access, at any time, without any burden or damage, to information on the purposes of storage, including the names of technical and institutional managers, potential risks and benefits, guarantees of quality of conservation and the integrity of their biological material.

5. To have access, at any time, without burden or damage, to the information associated with their biological material and be informed and guided by the researchers responsible for findings when the implications of this information may cause harm to their health, including genetic counseling when appropriate.

6. To have the privacy and confidentiality of their personal information guaranteed.

7. To be promptly informed of the dissolution of the repository in which their biological material is stored.

8. To be promptly informed of the transfer, loss, alteration or disposal of their biological material.

9. To designate legal representatives who may consent to the use and disposal of their biological material and have access to these materials and their associated information in case of death or disabling condition.

10. To be informed, at the time of the signing of the ICF, about the possibility of providing or not providing their consent for possible future uses in research of their data and biological material.

11. To be informed, at the time of signing the ICF, about the possibility of authorizing or not authorizing the submission of their data and biological material to a research center located outside the country.

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8. Biological material

Human biological material can be stored indefinitely in a biobank, which is an organized collection, without commercial purposes, of human biological material and associated information. This material is collected and stored for research purposes, according to predefined technical, ethical, and operational standards, and is under the responsibility and management of public or private institution. The material can also be stored in a biorepository, which is an organized collection, without commercial purposes, of human biological material and associated information. This material is collected and stored for the purpose of a specific research project, according to predefined technical, ethical, and operational standards, and is under the responsibility of a public or private institution and managed by the researcher. Storage can occur according to the schedule outlined in the approved research project.

At the end of the research project, human biological material may (i) remain stored, if in accordance with current and relevant legislation and ethical and regulatory guidelines, (ii) be transferred to another biorepository or biobank; or (iii) be discarded.

It is important to note that the biological material and the research data will be used exclusively for the purpose outlined in the respective project. An exception to this requirement occurs when, in the ICF, express authorization is granted so that they can be used in future research, for exclusively scientific purposes, provided that the provisions of this Law and the Regulation are observed.

The shipment and storage of human biological material to a research center located outside the country falls under the responsibility of the sponsor, subject to the following conditions:

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1. Adherence to national and international health legislation regarding the shipment and storage of biological material.

2. Guaranteeing access to and use of the biological material and its data for scientific purposes by researchers and national institutions.

3. Compliance with national legislation, particularly those prohibiting the patenting and commercialization of biological material.

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9. Publicity, Transparency, and Monitoring of Clinical Research

The research needs to be registered with the national research ethics body and its data should be regularly updated on a publicly accessible website.

The lead researcher is required to submit an annual progress report to the REC that approved the study, as well as report to the REC any serious adverse events and any violations of the research protocol. Any adverse events and protocol violations must also be reported to the health authority.

If a research study is discontinued, whether temporarily or permanently, this must be communicated to the REC that approved it. In this communication, the lead researcher must provide the technical and scientific justifications for the decision, along with a notification of discontinuation. A comprehensive report detailing the results achieved until the research was halted must be submitted to the committee within 30 business days. In the case of clinical trials, the lead researcher and the sponsor will also need to provide a plan for ongoing follow-up and necessary support for the participants of the discontinued research.

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10. Penalties

Conducting research involving human subjects in violation of the provisions of this Law is considered an ethical breach. The offender will be subject to disciplinary sanctions as outlined in the legislation of their respective professional council.

This in in addition to any civil and criminal liabilities.

Any violations of the sponsor's or researcher's responsibilities, transition plans for participants who continue to require care or health assistance, storage periods for biological material, and cases of serious adverse events not reported to the REC will subject the offender to the penalties provided for in Law #6,437, dated August 20, 1977, and in specific health regulations, without prejudice to civil and criminal liabilities.

The protection and anonymity of the personal data of research participants are regulated by this Law, applied in conjunction with the Brazilian General Data Protection Act (LGPD).

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11. Effective date

Although Law #14874/2024 was enacted on May 28, 2024, it will only come into force 90 days after its publication date.

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